Facile synthesis of selenium/sulfur-substituted 3-oxa-bicyclo[4.2.0]octa- 1(8),5-diene and tetrahydro-1 h -isochromene via sequential three-component conjugate addition/condensation/elimination/[2 + 2] or [4 + 2] cyclization Reactions

Article abstract of DOI:10.1021/jo101905r

An interesting sequential three-component reaction provides a facile synthesis of selenium/sulfur-substituted 3-oxabicyclo[4.2.0]octa-1(8),5-diene and tetrahydro-1H-isochromene from lithium alkylselenolates or alkylthiolates, 1-alkynylphosphine oxides, an

Full text of DOI:10.1021/jo101905r

pubs.acs.org/joc
bonds is of high interest in organic synthesis.1 Sequential
Facile Synthesis of Selenium/Sulfur-Substituted
3-Oxa-bicyclo[4.2.0]octa-1(8),5-diene and
Tetrahydro-1H-isochromene via Sequential
Three-Component Conjugate Addition/
Condensation/Elimination/[2 þ 2] or [4 þ 2]
Cyclization Reactions
reactions represent one of the most powerful tools for the
rapid construction of functionalized polycyclic molecules
via a process that often features the formation of multi-
bonds and stereocenters in one pot with high efficiency.2
Allenes have shown impressive synthetic potentials in
organic chemistry3 and many novel reactions were well
established in the past decades.4 [2þ2]5 cycloaddition of
ene/yne-allenes provides a convenient route for the con-
struction of cyclobutane and cyclobutene that are difficult
to synthesize, while [4 þ 2]6 cycloaddition of ene/yne-
allenes represents a powerful method for the synthesis of
cyclohexene. Recently, sequential reactions in which al-
lenes were generated in situ and underwent subsequent
processes have been intensively explored.7 Our group also
established a series of sequential reactions, leading to
the efficient synthesis of structurally complex poly-
cycles with 2,3-dihydrofuran units,8 fused dihydroisoben-
zofuran derivatives,9 polysubstituted pyridines, and iso-
quinolines.10
Jian Cao,† Xian Huang,†,‡,§ and Luling Wu*,†
†Department of Chemistry, Zhejiang University
(Xixi Campus), Hangzhou 310028, P. R. China, and
‡State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu,
Shanghai 200032, P. R. China. §Prof. Huang passed away on
March 6, 2010. He had been fully in charge of this project.
Prof. Luling Wu is working to finish Prof. Huang’s projects
with help from Prof. Shengming Ma.
wululing@zju.edu.cn
Received September 30, 2010
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vides a facile synthesis of selenium/sulfur-substituted
3-oxabicyclo[4.2.0]octa-1(8),5-diene and tetrahydro-1H-
isochromene from lithium alkylselenolates or alkylthio-
lates, 1-alkynylphosphine oxides, and aldehydes. The
sequential reaction proceeds via a conjugate addition/
condensation/elimination process to form the allene in-
termediate, which subsequently underwent [2 þ 2] or [4 þ
2] cyclization reaction to afford bicyclic frameworks.
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1440 J. Org. Chem. 2011, 76, 1440–1443
Published on Web 01/21/2011
DOI: 10.1021/jo101905r
r
2011 American Chemical Society

Cao et al.
JOCNote
SCHEME 1
SCHEME 2
reaction mixture of 1a, 2a, and 3a (1:1:1) in THF was stirred
at room temperature for 1 h, which was directly followed by
stirring under reflux for additional 12 h to afford the desired
product 5a in 52% yield.
Selenium11/sulfur12-substituted allenes have been used in a
wide range of applications in organic chemistry owing to
their utility as synthetic intermediates. Recently, our group
has reported a novel tandem three-component reaction
to afford selenium/sulfur-substituted allenes.13 In a contin-
uous effort to design sequential reactions via allene inter-
mediates,14 we envisioned a sequential three-component
conjugate addition/condensation/elimination/[2 þ 2] or
[4 þ 2] cycloaddition reaction: the intermediates A, which
would be generated in situ from conjugate addition of
lithium alkylselenolates or alkylthiolates 1 with 1-alkynyl-
phosphine oxides 2 and subsequent reaction with aldehydes
3, may undergo elimination reaction leading to the allenes B.
Then an intramolecular [2 þ 2] or [4 þ 2] cycloaddition
reaction may proceed to furnish selenium/sulfur-substituted
3-oxa-bicyclo[4.2.0]octa-1(8),5-diene and tetrahydro-1H-
isochromene, which are important and useful skeletons in
medicinal chemistry (Scheme 1).15 Apparently, by our strategy
three new carbon-carbon bonds and one carbon-selenium/
surfur bond would be formed in one pot, and two rings could
be efficiently assembled. Furthermore, the vinyl selenide/
sufide products are useful intermediates for many trans-
formations.16 Herein, we report our results on this novel
sequential three-component reaction.
Further screening of reaction conditions demonstrated
that DME was the most suitable solvent for this reaction.
We then carried out the reaction using various lithium
alkylselenolates or alkylthiolates 1 with 1-alkynylphos-
phine oxides 2 and aldehydes 3. As indicated in Table 1,
the reactions proceeded smoothly to afford the corre-
sponding 3-oxabicyclo[4.2.0]octa-1(8),5-dienes 5 in mod-
erate to good yields. Both lithium alkylselenolates and
alkylthiolates underwent the reaction smoothly (Table 1,
entries 1, 5 and 10). R2 in 1-alkynylphosphine oxides 2
can be a substituted phenyl group (entries 1, 8, and 9).
Various aryl and R,β-unsaturated enals 3 worked (entries
1-7 and 11-14).
When R2 or R3 was the alkyl group, although allene 4
could be obtained, the [2 þ 2] reaction gave a complex
mixture (Scheme 3).
Inspired by the above results, we expanded the reaction
scope by replacing the triple bond substituted with R2 in
1-alkynylphosphine oxides 2 with a double bond. However,
the allene 4d obtained from the reaction of 1a, 6a, and 3a
gradually decomposed upon heating in refluxing DME for
40 h, and no expected product was found (Scheme 4).
Interestingly, when R,β-unsaturated aldehyde 3f was em-
ployed, [4 þ 2] reaction occurred to afford tetrahydro-1H-
isochromene 7a in 61% yield.
We then carried out the reaction using various lithium
alkylselenolates or alkylthiolates 1 with 1-alkynylphosphine
oxides 6 and R,β-unsaturated enals 3, and the results are
shown in Table 2.
All products above were afforded as a single stereoisomer,
and the stereochemistry of these compounds was established
by the NOESY study of 7f and 7g (Figure 1 and Supporting
Information). Similar stereoselectivity of the intramolecular
Diels-Alder reaction of vinylallene has been reported in
several cases.17
We initiated our study by attempting the reaction of 1a, 2a,
and 3a (1:1:1) (Scheme 2). After the mixture was stirred at
room temperature for 1 h, the reaction gave allene 4a in 75%
yield and no [2 þ 2] product 5a was detected. Fortunately,
simply refluxing the solution of 4a in THF resulted in com-
plete conversion to the desired cycloaddition bicyclic prod-
uct 5a in 72% yield. Based on these results, we performed
the sequential three-component reaction in one pot. The
(13) (a) Huang, X.; Xiong, Z. Chem. Commun. 2003, 1714. (b) Huang, X.;
Xiong, Z. Tetrahedron Lett. 2003, 44, 5913.
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Chen, L.; Huang, X. Adv. Synth. Catal. 2009, 351, 2833.
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Vinyl selenides are useful intermediates for many trans-
formations in organic chemistry. Therefore, compound 5f
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J. Org. Chem. Vol. 76, No. 5, 2011 1441

Cao et al.
JOCNote
TABLE 1. Synthesis of 3-Oxabicyclo[4.2.0]octa-1(8),5-dienes 5a
entry
R1X (1)
R2 (2)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
p-MeC6H4 (2b)
p-ClC6H4 (2c)
Ph (2a)
R3 (3)
p-BrC6H4 (3a)
p-ClC6H4 (3b)
p-MeOC6H4 (3c)
p-MeC6H4 (3d)
p-MeOC6H4CHdCH(E) (3e)
PhCHdCH(E) (3f)
MeCHdCH(E) (3g)
PhCHdCH(E) (3f)
PhCHdCH(E) (3f)
p-BrC6H4 (3a)
yield of 5 (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
MeSe (1a)
MeSe (1a)
MeSe (1a)
MeSe (1a)
n-BuSe (1b)
MeSe (1a)
MeSe (1a)
n-BuSe (1b)
n-BuSe (1b)
MeS (1c)
59 (5a)
62 (5b)
70 (5c)
65 (5d)
55 (5e)
52 (5f)
40 (5g)
50 (5h)
53 (5i)
49 (5j)
44 (5k)
57 (5l)
53 (5m)
42 (5n)
MeSe (1a)
MeSe (1a)
MeS (1c)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
p-FC6H4 (3h)
m-ClC6H4 (3i)
Ph (3j)
PhCHdCH(E) (3f)
MeS (1c)
aUnless otherwise specified, the reaction was carried out using 1 (1.0 equiv), 2 (1.0 equiv), and 3 (1.0 equiv) at rt for 1 h and then under reflux
for 8-12 h.
SCHEME 3
TABLE 2. Synthesis of Tetrahydro-1H-isochromenes 7a
entry
R1X (1)
R5 (3)
Ph (3f)
p-BrC6H4 (3k)
p-MeOC6H4 (3e)
Ph (3f)
Me (3g)
Ph (3f)
Ph (3f)
R4 (6)
yield of 7 (%)
1
2
3
4
n-BuSe (1b)
n-BuSe (1b)
n-BuSe (1b)
n-BuS (1d)
MeSe (1a)
MeS (1c)
H (6a)
H (6a)
H (6a)
H (6a)
H (6a)
H (6a)
Me (6b)
61 (7a)
57 (7b)
63 (7c)
55 (7d)
39 (7e)
49 (7f)
41 (7g)
SCHEME 4
5
6
7b
MeSe (1a)
aUnless otherwise specified, the reaction was carried out using 1
(1.0 equiv), 6 (1.0 equiv), and 3 (1.0 equiv) at rt for 1 h and then under
reflux for 40-50 h. bThe reaction was carried out in dioxane at rt for 1 h
and then under reflux for 48 h.
was selected for study of the Kumada cross-coupling reaction
with Grignard reagent.18 Under classical conditions of the
Kumada coupling reaction, 5f reacted smoothly with ethyl-
magnesium bromide at rt in THF to afford the cross-
coupling product 8 in 53% yield (Scheme 5).
In conclusion, we have realized a sequential three-compo-
nent Michael addition/aldol/Horner-Wadsworth-Emmons
/[2 þ 2] or [4 þ 2] cyclization reaction, affording an efficient
and stereoselective synthesis of bicyclic skeletons selenium/
sulfur-substituted 3-oxa-bicyclo[4.2.0]octa-1(8),5-dienes and
tetrahydro-1H-isochromenes from readily available lithium
alkylselenolates or alkylthiolates, 1-alkynylphosphine oxi-
des, and aldehydes. Furthermore, Kumada cross-coupling
FIGURE 1. NOESY of 7f and 7g.
reaction of the product vinyl selenide was conducted to show
the potential of the products. Experiments designed to
further explore the reaction scope are currently underway.
Experimental Section
Typical Procedure for the Synthesis of 3-Oxabicyclo[4.2.0]
octa-1(8),5-diene. (See 5a, Table 1, entry 1 as an example.) To
a suspension of Se powder (79 mg, 1 mmol) in DME (5 mL) was
1442 J. Org. Chem. Vol. 76, No. 5, 2011

Cao et al.
JOCNote
SCHEME 5
dd, J = 15.6 and 1.6 Hz), 4.62 (1H, dd, J = 15.6 and 1.2 Hz),
4.27 (1H, d, J = 15.2 Hz), 4.23 (1H, d, J = 15.2 Hz), 1.91 (3H, s);
13C NMR (100 MHz, CDCl3) δ 141.0, 140.0, 139.0, 137.9, 133.0,
131.6, 129.5, 128.6, 127.7, 126.3, 120.7, 108.9, 67.9, 62.5, 54.6,
5.4; MS (m/z) 432 (Mþ); IR (neat, cm-1) 2929, 2822, 1592, 1487,
1271, 1071, 1010; HRMS calcd for C20H17OSeBr (Mþ)
431.9628, found 431.9640.
added MeLi (0.625 mL, 1 mmol, 1.6 mmol/mL in hexane) under
nitrogen atmosphere, and the mixture was stirred at rt for 5 min.
Then, the above-formed solution of MeSeLi 1a was added to a
solution of 1-alkynylphosphine oxide 2a (370 mg, 1 mmol) and
aldehyde 3a (184 mg, 1 mmol) in DME (5 mL) under nitrogen
atmosphere, and the mixture was stirred at rt for 1 h and then
under reflux for 10 h. After filtration and evaporation, the
residue was purified by flash chromatography on silica gel
(eluent: petroleum ether/ethyl acetate = 50:1) to afford 5a
(255 mg, 59%): liquid; 1H NMR (400 MHz, CDCl3) δ 7.41
(2H, d, J = 8.4 Hz), 7.22-7.28 (4H, m), 7.15-7.19 (1H, m), 7.07
(2H, d, J = 7.2 Hz), 4.83 (1H, dd, J = 1.6 and 1.2 Hz), 4.77 (1H,
Acknowledgment. We are grateful to the National Natur-
al Science Foundation of China (Project Nos. 20732005
and 20872127), the National Basic Research Program of
China (973 Program, 2009CB825300), and the Fundamental
Research Funds for the Central Universities for financial
support.
Supporting Information Available: Spectroscopic data for
4a-d, 5a-n, 7a-g, and 8. NOESY spectra of 7f and 7g. Detailed
experimental procedures. This material is available free of
charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 76, No. 5, 2011 1443